Serotonin (5-hydroxytryptamine (5-HT)) is an important neurotransmitter that regulates multiple events in the central nervous system. Many of the 5-HT functions are mediated via G protein-coupled receptors that are coupled to multiple heterotrimeric G proteins, including Gs, Gi, and Gq subfamilies (Martin, G. R., Eglen, R. M., Hamblin, M. W., Hoyer, D., and Yocca, F. (1998)Trends Pharmacol. Sci. 19, 2–4). Here we show for the first time that the 5-hydroxytryptamine 4(a) receptor (5-HT4(a)) is coupled not only to heterotrimeric Gs but also to G13 protein, as assessed both by biochemical and functional assays. Using reconstitution of 5-HT4(a) receptor with different G proteins in Spodoptera frugiperda (Sf.9) cells, we have proved that agonist stimulation of receptor-induced guanosine 5′-(3-O-thio)triphosphate binding to Gα13protein. We then determined that expression of 5-HT4(a)receptor in mammalian cells induced constitutive- as well as agonist-promoted activation of a transcription factor, serum response element, through the activation of Gα13 and RhoA. Finally, we have determined that expression of 5-HT4(a)receptor in neuroblastoma × glioma NIE-115 cells cause RhoA-dependent neurite retraction and cell rounding under basal conditions and after agonist stimulation. These data suggest that by activating 5-HT4(a) receptor-G13 pathway, serotonin plays a prominent role in regulating neuronal architecture in addition to its classical role in neurotransmission.
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Published, JBC Papers in Press, March 28, 2002, DOI 10.1074/jbc.M112216200
These studies were supported by National Institutes of Health Grant GM56159 (to T. V.-Y.), by funding from the Medical School at the University of Göttingen, and by Deutsche Forschungsgemeinschaft Grant PO 732/1-1 (to E. G. P.). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
